Role of ROS producing NADPH-dependent oxidases (NOX) in β-cell dysfunction

Loss of pancreatic islet function is a central hallmark in the pathogenesis of T2DM. In addition, it may be that also β-cell loss occurs in T2DM, and that this starts, after an initial phase of hyperinsulinemia, relatively late in the progression of the disease. The mechanisms resulting in beta cell failure in T2DM are not clear, but accumulating evidence point to a central role of oxidative stress as a result of overproduction of reactive oxygen species (ROS) (Figure 1).

The excessive production and accumulation of ROS is, at least in part, due to hyperactivity of the NADPH oxidases (NOX). The NOX family consists of seven isoforms (NOX1-5 and DUOX1-2), which perform normal cellular functions at basal conditions, but when persistently activated produce harmful levels of ROS. Hyperactivity of some of the isoforms has been found to be an important driver in a number of diseases including diabetes and diabetes complications [11]. The present project will explore ways to protect against β-cell oxidative stress and deterioration by inhibiting NOX, and to define T2DM patient groups that would particularly benefit from treatment with such inhibitors. Novel NOX inhibitors are available to us via Glucox Biotech, a company that possess fundamental patents, granted in the US and in Europe and pending in Japan, which cover the rights to develop anti-diabetes drugs aimed to inhibit NOX. Glucox Biotech also owns international (PCT) substance patent applications on its first and second compound generation.